tbuckley/cabot-search huggingface dataset:
A CRISPRi/a platform in human iPSC-derived microglia uncovers regulators of disease states
Authors: Nina M. Dräger, Sydney M. Sattler, Cindy Tzu-Ling Huang, Olivia M. Teter, Kun Leng, Sayed Hadi Hashemi, Jason Hong, Giovanni Aviles, Claire D. Clelland, Lihong Zhan, Joe C. Udeochu, Lay Kodama, Andrew B. Singleton, Mike A. Nalls, Justin Ichida, Michael E. Ward, Faraz Faghri, Li Gan, Martin Kampmann
Journal: Nature Neuroscience (2022)

Microglia are emerging as key drivers of neurological diseases. However, we lack a systematic understanding of the underlying mechanisms. Here, we present a screening platform to systematically elucidate functional consequences of genetic perturbations in human induced pluripotent stem cell-derived microglia. We developed an efficient 8-day protocol for the generation of microglia-like cells based on the inducible expression of six transcription factors. We established inducible CRISPR interference and activation in this system and conducted three screens targeting the 'druggable genome'. These screens uncovered genes controlling microglia survival, activation and phagocytosis, including neurodegeneration-associated genes. A screen with single-cell RNA sequencing as the readout revealed that these microglia adopt a spectrum of states mirroring those observed in human brains and identified regulators of these states. A disease-associated state characterized by osteopontin (SPP1) expression was selectively depleted by colony-stimulating factor-1 (CSF1R) inhibition. Thus, our platform can systematically uncover regulators of microglial states, enabling their functional characterization and therapeutic targeting.
Adverse Outcomes of Underuse of β-Blockers in Elderly Survivors of Acute Myocardial Infarction
Authors: Stephen B. Soumerai
Journal: JAMA (1997)

<h3>Objectives.</h3> —To study determinants and adverse outcomes (mortality and rehospitalization) of β-blocker underuse in elderly patients with myocardial infarction; and whether the relative risks (RRs) of survival associated with β-blocker use were comparable to those reported in the large randomized controlled trials (RCTs). <h3>Setting.</h3> —New Jersey Medicare population. <h3>Design.</h3> —Retrospective cohort design using linked Medicare and drug claims data from 1987 to 1992. <h3>Patients.</h3> —Statewide cohort of 5332 elderly 30-day acute myocardial infarction (AMI) survivors with prescription drug coverage, of whom 3737 were eligible for β-blockers. <h3>Main Outcome Measures.</h3> —β-Blocker and calcium channel blocker use in the first 90 days after discharge and mortality rates and cardiac hospital readmissions over the 2-year period after discharge, controlling for sociodemographic and baseline risk variables. <h3>Results.</h3> —Only 21% of eligible patients received β-blocker therapy; this rate remained unchanged from 1987 to 1991. Patients were almost 3 times more likely to receive a new prescription for a calcium channel blocker than for a new β-blocker after their AMIs. Advanced age and calcium channel blocker use predicted underuse of β-blockers. Controlling for other predictors of survival, the mortality rate among β-blocker recipients was 43% less than that for nonrecipients (RR=0.57; 95% confidence interval [CI], 0.47-0.69). Effects on mortality were substantial in all age strata (65-74 years, 75-84 years, and ≥85 years) and consistent with the results for elderly subgroups of 2 large RCTs. β-Blocker recipients were rehospitalized 22% less often than nonrecipients (RR=0.78; 95% CI, 0.67-0.90). Use of a calcium channel blocker instead of a β-blocker was associated with a doubled risk of death (RR=1.98; 95% CI, 1.44-2.72), not because calcium channel blockers had a demonstrable adverse effect, but because they were substitutes for β-blockers. <h3>Conclusions.</h3> —β-Blockers are underused in elderly AMI survivors, leading to measurable adverse outcomes. These data suggest that the survival benefits of β-blockade after an AMI may extend to eligible patients older than 75 years, a group that has been excluded from RCTs.
Intestinal microbiota modulates pancreatic carcinogenesis through intratumoral natural killer cells
Authors: Qin Yu, Rachel C. Newsome, Mark Beveridge, Maria C. Hernandez, Raad Z. Gharaibeh, Christian Jobin, Ryan M. Thomas
Journal: Gut Microbes (2022)

Preclinical data demonstrate that the gut microbiota can promote pancreatic ductal adenocarcinoma (PDAC), but mechanisms remain unclear. We hypothesized that intestinal microbiota alters anti-tumor innate immunity response to facilitate PDAC progression. Human PDAC L3.6pl cells were heterotopically implanted into Rag1-/- mice after microbiota depletion with antibiotics, while syngeneic murine PDAC Pan02 cells were implanted intrapancreatic into germ-free (GF) C57BL/6 J mice. Natural killer (NK) cells and their IFNγ expression were quantitated by flow cytometry. NK cells were depleted in vivo using anti-Asialo GM1 antibody to confirm the role of NK cells. Bacteria-free supernatant from SPF and GF mice feces was used to test its effect on NK-92MI cell anti-tumor response in vitro. SPF and ex-GF mice (reconstituted with SPF microbiota) developed larger PDAC tumors with decreased NK cell tumor infiltration and IFNγ expression versus GF-Rag1-/-. Microbiota-induced PDAC tumorigenesis was attenuated by antibiotic exposure, a process reversed following NK cell depletion in both Rag1-/- and C57BL/6 J mice. Compared to GF, SPF-Rag1-/- abiotic stool culture supernatant inhibited NK-92MI cytotoxicity, migration, and anti-cancer related gene expression. Gut microbiota promotes PDAC tumor progression through modulation of the intratumoral infiltration and activity of NK cells.
The Causes of Cancer: Quantitative Estimates of Avoidable Risks of Cancer in the United States Today
Authors: Richard Doll, Richard Peto
Journal: JNCI Journal of the National Cancer Institute (1981)

Evidence that the various common types of cancer are largely avoidable diseases is reviewed. Life-style and other environmental factors are divided into a dozen categories, and for each category the evidence relating those particular factors to cancer onset rates is summarized. Where possible, an estimate is made of the percentage of current U.S. cancer mortality that might have been caused or avoided by that category of factors. These estimates are based chiefly on evidence from epidemiology, as the available evidence from animal and other laboratory studies cannot provide reliable human risk assessments. By far the largest reliably known percentage is the 30% of current U.S. cancer deaths that are due to tobacco, although it is possible that some nutritional factor(s) may eventually be found to be of comparable importance. The percentage of U.S. cancer deaths that are due to tobacco is still increasing, and must be expected to continue to increase for some years yet due to the delayed effects of the adoption of cigarettes in earlier decades. Trends in mortality and in onset rates for many separate types of cancer are studied in detail in appendixes to this paper. Biases in the available data on registration of new cases produce apparent trends in cancer incidence which are spurious. Biases also produce spurious trends in cancer death certification rates, especially among old people. In (and before) middle age, where the biases are smaller, there appear to be a few real increases and a few real decreases in mortality from some particular types of cancer, but there is no evidence of any generalized increase other than that due to tobacco. Moderate increases or decreases due to some new agent(s) or habit(s) might of course be overlooked in such large-scale analyses. But, such analyses do suggest that, apart from cancer of the respiratory tract, the types of cancer that are currently common are not peculiarly modern diseases and are likely to depend chiefly on some longestablished factor(s). (A prospective study utilizing both questionnaires and stored blood and other biological materials might help elucidate these factors.) The proportion of current U.S. cancer deaths attributed to occupational factors is provisionally estimated as 4% (lung cancer being the major contributor to this). This is far smaller than has recently been suggested by various U.S. Government agencies. The matter could be resolved directly by a “case-control” study of lung cancer two or three times larger than the recently completed U.S. National Bladder Cancer Study but similar to it in methodology and unit costs; there are also other reasons for such a study. A fuller summary of conclusions and recommendations comprises the final section of this report.
Social Vulnerability and Risk of Nonrelapse Mortality After Allogeneic Hematopoietic Cell Transplantation
Authors: Rusha Bhandari, Jennifer Berano Teh, Tianhui He, Ryotaro Nakamura, Andrew S Artz, Marta M Jankowska, Stephen J Forman, F Lennie Wong, Saro H Armenian
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Risk of nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT) is high. Patient-level clinical prediction models such as the HCT–comorbidity index (HCT-CI) help identify those at increased risk for NRM, but the independent contribution of social determinants of health on HCT outcomes is not well characterized. Methods This study included 1602 patients who underwent allogeneic HCT between 2013 and 2019 at City of Hope. Census tract–level social vulnerability was measured using the social vulnerability index (SVI). Fine-Gray multivariable regression evaluated the association between SVI and 1-year NRM. Subgroup analysis examined risk of NRM across combined SVI and HCT-CI categories and by race and ethnicity. Results Cumulative incidence of 1-year NRM after HCT was 15.3% (95% confidence interval [CI] = 13.6% to 17.1%). In multivariable analysis, patients in the highest SVI tertile (highest social vulnerability) had a 1.4-fold risk (subdistribution hazard ratio [sHR] = 1.36, 95% CI = 1.04 to 1.78) of NRM compared with individuals in the lower tertiles; patients in the highest SVI tertile who also had elevated (≥3) HCT-CI scores had the highest risk (sHR = 1.81, 95% CI = 1.26 to 2.58) of 1-year NRM (reference: lower SVI tertiles and HCT-CI &amp;lt; 3). High social vulnerability was associated with risk of 1-year NRM in Asian (sHR = 2.03, 95% CI = 1.09 to 3.78) and Hispanic (sHR = 1.63, 95% CI = 1.04 to 2.55) but not non-Hispanic White patients. Conclusions High social vulnerability independently associated with 1-year NRM after HCT, specifically among minority populations and those with a high comorbidity burden at HCT. These findings may inform targeted approaches for needs assessment during and after HCT, allowing for timely interventions to improve health outcomes in at-risk patients.
Ancient Human Endogenous Retroviruses Contribute to Genetic Evolution and Regulate Cancer Cell Type–Specific Gene Expression
Authors: Mingyue Chen, Lei Jia, Xiaofeng Zheng, Mingshu Han, Lin Li, Lei Zhang
Journal: Cancer Research (2022)

Human endogenous retroviruses (HERV), a type of transposable elements (TE), play crucial roles in human placental morphogenesis, immune response, and cancer progression. Emerging evidence suggests that TEs have been a rich source of regulatory elements in the human genome, but little is known about the global impact of HERVs on transcriptional networks in cancer. Using genome-wide approaches, we show that HERVs are composed primarily of three ancient superfamilies: ERVL-MaLR, ERVL, and ERV1. This analysis suggests that the integration of exonic, intronic, and intergenic HERVs, as well as human or Hominidae gene-specific HERVs, contributes to human genomic innovation. HERVs exonized in genes are located mainly in the 3' untranslated region (UTR) or 3' end and participate in basic biological processes. Active HERVs are located mainly in intronic and intergenic regions and tend to function as enhancers and contribute to cancer cell type-specific gene expression. More importantly, HERVs may also define chromatin topologically associating domain (TAD) and loop boundaries in a cell type-specific manner. Taken together, these findings reveal that ancient HERV elements are a source of diverse regulatory sequences, including 3' UTRs, 5' UTRs, promoters, and enhancers, and they contribute to genetic innovation and cancer cell type-specific gene expression, highlighting the previously underestimated importance of these elements.Genome-wide analyses show that human endogenous retroviruses mediate cancer cell type-specific gene expression, epigenetic modification, and 3D chromatin architecture, elucidating the relationship between HERVs and diverse cancers.
Inhibition of Melanoma Cell–Intrinsic Tim-3 Stimulates MAPK-Dependent Tumorigenesis
Authors: Tobias Schatton, Yuta Itoh, Christina Martins, Erik Rasbach, Praveen Singh, Mariana Silva, Kyla Mucciarone, Markus V. Heppt, Jenna Geddes-Sweeney, Kate Stewart, Anne Brandenburg, Jennifer Liang, Charles J. Dimitroff, Martin C. Mihm, Jennifer Landsberg, Christoph Schlapbach, Christine G. Lian, George F. Murphy, Thomas S. Kupper, Matthew R. Ramsey, Steven R. Barthel
Journal: Cancer Research (2022)

T-cell immunoglobulin mucin family member 3 (Tim-3) is an immune checkpoint receptor that dampens effector functions and causes terminal exhaustion of cytotoxic T cells. Tim-3 inhibitors are under investigation in immuno-oncology (IO) trials, because blockade of T-cell-Tim-3 enhances antitumor immunity. Here, we identify an additional role for Tim-3 as a growth-suppressive receptor intrinsic to melanoma cells. Inhibition of melanoma cell-Tim-3 promoted tumor growth in both immunocompetent and immunocompromised mice, while melanoma-specific Tim-3 overexpression attenuated tumorigenesis. Ab-mediated Tim-3 blockade inhibited growth of immunogenic murine melanomas in T-cell-competent hosts, consistent with established antitumor effects of T-cell-Tim-3 inhibition. In contrast, Tim-3 Ab administration stimulated tumorigenesis of both highly and lesser immunogenic murine and human melanomas in T-cell-deficient mice, confirming growth-promoting effects of melanoma-Tim-3 antagonism. Melanoma-Tim-3 activation suppressed, while its blockade enhanced, phosphorylation of pro-proliferative downstream MAPK signaling mediators. Finally, pharmacologic MAPK inhibition reversed unwanted Tim-3 Ab-mediated tumorigenesis in T-cell-deficient mice and enhanced desired antitumor activity of Tim-3 interference in T-cell-competent hosts. These results identify melanoma-Tim-3 blockade as a mechanism that antagonizes T-cell-Tim-3-directed IO therapeutic efficacy. They further reveal MAPK targeting as a combination strategy for circumventing adverse consequences of unintended melanoma-Tim-3 inhibition. Tim-3 is a growth-suppressive receptor intrinsic to melanoma cells, the blockade of which promotes MAPK-dependent tumorigenesis and thus counteracts antitumor activity of T-cell-directed Tim-3 inhibition.
Using molecular simulation to understand the skin barrier
Authors: Parashara Shamaprasad, Chloe O. Frame, Timothy C. Moore, Alexander Yang, Christopher R. Iacovella, Joke A. Bouwstra, Annette L. Bunge, Clare McCabe
Journal: Progress in Lipid Research (2022)

Skin's effectiveness as a barrier to permeation of water and other chemicals rests almost entirely in the outermost layer of the epidermis, the stratum corneum (SC), which consists of layers of corneocytes surrounded by highly organized lipid lamellae. As the only continuous path through the SC, transdermal permeation necessarily involves diffusion through these lipid layers. The role of the SC as a protective barrier is supported by its exceptional lipid composition consisting of ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs) and the complete absence of phospholipids, which are present in most biological membranes. Molecular simulation, which provides molecular level detail of lipid configurations that can be connected with barrier function, has become a popular tool for studying SC lipid systems. We review this ever-increasing body of literature with the goals of (1) enabling the experimental skin community to understand, interpret and use the information generated from the simulations, (2) providing simulation experts with a solid background in the chemistry of SC lipids including the composition, structure and organization, and barrier function, and (3) presenting a state of the art picture of the field of SC lipid simulations, highlighting the difficulties and best practices for studying these systems, to encourage the generation of robust reproducible studies in the future. This review describes molecular simulation methodology and then critically examines results derived from simulations using atomistic and then coarse-grained models.
Re: Kathia De Man, Nick Van Laeken, Vanessa Schelfhout, et al. 18F-PSMA-11 Versus 68Ga-PSMA-11 Positron Emission Tomography/Computed Tomography for Staging and Biochemical Recurrence of Prostate Cancer: A Prospective Double-blind Randomised Cross-over Trial. Eur Urol. 2022;82:501–509
Authors: Francesco Montorsi, Giorgio Gandaglia, Daniele Robesti, Federico Dehò, Alberto Briganti
Journal: European Urology (2022)
A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma
Authors: Sharmistha Pal, Jakub P. Kaplan, Huy Nguyen, Sylwia A. Stopka, Milan R. Savani, Michael S. Regan, Quang-De Nguyen, Kristen L. Jones, Lisa A. Moreau, Jingyu Peng, Marina G. Dipiazza, Andrew J. Perciaccante, Xiaoting Zhu, Bradley R. Hunsel, Kevin X. Liu, Sanda Alexandrescu, Rachid Drissi, Mariella G. Filbin, Samuel K. McBrayer, Nathalie Y.R. Agar, Dipanjan Chowdhury, Daphne A. Haas-Kogan
Journal: Cancer Cell (2022)
YES1 Is a Druggable Oncogenic Target in SCLC
Authors: Esther Redin, Eva M. Garrido-Martin, Karmele Valencia, Miriam Redrado, Jose Luis Solorzano, Rafael Carias, Mirari Echepare, Francisco Exposito, Diego Serrano, Irene Ferrer, Angel Nunez-Buiza, Irati Garmendia, Juana M. García-Pedrero, Alfonso Gurpide, Luis Paz-Ares, Katerina Politi, Luis M. Montuenga, Alfonso Calvo
Journal: Journal of Thoracic Oncology (2022)
Real-world clinical outcomes with avelumab in patients with Merkel cell carcinoma treated in the USA: a multicenter chart review study
Authors: Shailender Bhatia, Paul Nghiem, S Phani Veeranki, Alejandro Vanegas, Kristina Lachance, Lisa Tachiki, Kevin Chiu, Emily Boller, Murtuza Bharmal
Journal: Journal for ImmunoTherapy of Cancer (2022)

Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous neuroendocrine neoplasm with annual incidence rates of 0.13-1.6 cases/100,000/year worldwide as of 2018. Chemotherapy for metastatic MCC (mMCC) has high objective response rates (ORRs), but responses are not durable and overall survival (OS) is poor. Avelumab (anti-programmed death-ligand 1) has demonstrated meaningful survival benefit and durable responses in clinical trials for mMCC. This study investigated real-world clinical outcomes in avelumab-treated patients with advanced (stage IIIB/IV) MCC in US academic medical centers.We conducted a retrospective chart review of patients with advanced MCC who initiated avelumab between March 1, 2017, and July 31, 2019, at six US academic centers. Data were requested for eligible patients from index date through December 31, 2020. Descriptive analyses were conducted to assess demographic and clinical characteristics, real-world ORR (rwORR), real-world duration of response, real-world progression-free survival (rwPFS), and OS.Ninety patients with advanced MCC (82%, stage IV; 18%, stage IIIB) received avelumab. Median follow-up was 20.8 months (95% CI: 19.1 to 24.2). Median age was 68 years (range, 48-83), and the majority of patients were men (58%) and white (93%). The primary tumor was most commonly located on the lower limb (38%), with metastases mostly located in lymph nodes (68%), lung (52%), and viscera (52%). Approximately 42% and 26% of patients had an Eastern Cooperative Oncology Group performance status of 2 and 3, respectively. Seventy-three patients (81%) received avelumab as first-line treatment of advanced MCC, while 17 (19%) received avelumab as second-line or later treatment. The median duration of avelumab treatment was 13.5 months (95% CI: 6.4 to 30.6), with 42% of patients still receiving avelumab by the end of follow-up. Patients with avelumab treatment had an rwORR of 73% (95% CI: 64 to 83), median rwPFS of 24.4 months (95% CI: 8.31 to not estimable (NE)), and median OS of 30.7 months (95% CI: 11.2 to NE).This real-world study of patients with advanced MCC demonstrated that avelumab treatment resulted in a high response rate with durable responses and prolonged survival. The study findings validate the results demonstrated in prospective clinical trials and other observational studies.
Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39 – a promising target for cancer immunotherapy
Authors: Laura Schäkel, Salahuddin Mirza, Riekje Winzer, Vittoria Lopez, Riham Idris, Haneen Al-Hroub, Julie Pelletier, Jean Sévigny, Eva Tolosa, Christa E Müller
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background An important mechanism, by which cancer cells achieve immune escape, is the release of extracellular adenosine into their microenvironment. Adenosine activates adenosine A 2A and A 2B receptors on immune cells constituting one of the strongest immunosuppressive mediators. In addition, extracellular adenosine promotes angiogenesis, tumor cell proliferation, and metastasis. Cancer cells upregulate ectonucleotidases, most importantly CD39 and CD73, which catalyze the hydrolysis of extracellular ATP to AMP (CD39) and further to adenosine (CD73). Inhibition of CD39 is thus expected to be an effective strategy for the (immuno)therapy of cancer. However, suitable small molecule inhibitors for CD39 are not available. Our aim was to identify drug-like CD39 inhibitors and evaluate them in vitro. Methods We pursued a repurposing approach by screening a self-compiled collection of approved, mostly ATP-competitive protein kinase inhibitors, on human CD39. The best hit compound was further characterized and evaluated in various orthogonal assays and enzyme preparations, and on human immune and cancer cells. Results The tyrosine kinase inhibitor ceritinib, a potent anticancer drug used for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer, was found to strongly inhibit CD39 showing selectivity versus other ectonucleotidases. The drug displays a non-competitive, allosteric mechanism of CD39 inhibition exhibiting potency in the low micromolar range, which is independent of substrate (ATP) concentration. We could show that ceritinib inhibits ATP dephosphorylation in peripheral blood mononuclear cells in a dose-dependent manner, resulting in a significant increase in ATP concentrations and preventing adenosine formation from ATP. Importantly, ceritinib (1–10 µM) substantially inhibited ATP hydrolysis in triple negative breast cancer and melanoma cells with high native expression of CD39. Conclusions CD39 inhibition might contribute to the effects of the powerful anticancer drug ceritinib. Ceritinib is a novel CD39 inhibitor with high metabolic stability and optimized physicochemical properties; according to our knowledge, it is the first brain-permeant CD39 inhibitor. Our discovery will provide the basis (i) to develop more potent and balanced dual CD39/ALK inhibitors, and (ii) to optimize the ceritinib scaffold towards interaction with CD39 to obtain potent and selective drug-like CD39 inhibitors for future in vivo studies.